Robust microtubule dynamics facilitate low-tension kinetochore detachment in metaphase

Abstract

During mitosis, sister chromatids are stretched apart at their centromeres via their attachment to oppositely oriented kinetochore microtubules. This stretching generates inwardly directed tension across the separated sister centromeres. The cell leverages this tension signal to detect and then correct potential errors in chromosome segregation, via a mechanical tension signaling pathway that detaches improperly attached kinetochores from their microtubules. However, the sequence of events leading up to these detachment events remains unknown. In this study, we used microfluidics to sustain and observe low-tension budding yeast metaphase spindles over multiple hours, allowing us to elucidate the tension history prior to a detachment event. We found that, under conditions in which kinetochore phosphorylation weakens low-tension kinetochore-microtubule connections, the mechanical forces produced via the dynamic growth and shortening of microtubules is required to efficiently facilitate detachment events. Our findings underscore the critical role of robust kinetochore microtubule dynamics in ensuring the fidelity of chromosome segregation during mitosis.

Chromosome size-dependent polar ejection force impairs mammalian mitotic error correction

“…3G), suggesting that beyond a certain tension threshold, additional tension will not slow alignment further but may impact the probability of error detection. This is consistent with work that shows that the tension state impacts kinetochore detachment probability (Chen et al, 2021; De Regt et al, 2022; Miller et al, 2019, 2016; Parmar et al, 2023; Sarangapani et al, 2013). Additionally, attachment stability and error correction efficiency may also be linked to chromosome position in the spindle, leading to differential access to known regulators like Aurora A kinase (Eibes et al, 2023; Ye et al, 2015).…”

Mechanical coupling coordinates microtubule growth

“…For all the experiments described below, F TOT = 8 pN. Thus, each microtubule generally experiences between 1 and 7 pN of tension, close to the estimated average of 4–6 pN experienced by kinetochore-microtubules in budding yeast ( Chacón et al, 2014 ; Parmar et al, 2023 ).…”

Mechanical coupling coordinates microtubule growth

“…For all the experiments described below, F TOT = 8 pN. Thus, each microtubule generally experiences between 1 and 7 pN of tension, close to the estimated average of 4 to 6 pN experienced by kinetochore-microtubules in budding yeast (Chacon et al, 2014;Parmar et al, 2023).…”